Superiority of interleukin-12-transduced murine lung cancer cells to GM-CSF or B7-1 (CD80) transfectants for therapeutic antitumor immunity in syngeneic immunocompetent mice.
Interleukin-12 (IL-12) is a heterodimeric cytokine that consists of p40 and p35 subunits. IL-12 has been regarded as a potent inducer of host antitumor immunity through interferon-gamma (IFN-gamma) production and development of Th1 helper T cells from Th0 cells. Here, we demonstrate the immunomodulatory actions of an IL-12-transduced murine lung cancer cell line, Lewis lung carcinoma (LLC) (LLC/IL12) cells, in syngeneic C57BL/6 mice. We also report on their therapeutic potency. Three LLC/IL12 cells producing different levels of IL-12 were cloned and found to have diminished tumorigenicity in C57BL/6 mice depending on their level of IL-12 production. In vivo depletion assay demonstrated that the loss of tumorigenicity of LLC/IL12 depended on both CD4+ and CD8+ T cells, and that natural killer (NK) cells were involved, especially in the early phase of immunity. The strong systemic antitumor immunity against challenge with wild type LLC (LLC/wt) cells was also induced by LLC/IL12 cells. The systemic antitumor memory was found to be dependent mainly on the CD4+ T-cell subset. 51Cr-release assay revealed that the killer activity consisted of a specific killer activity directed at the parental LLC/wt cells and a nonspecific killer activity directed at both LLC/wt and syngeneic EL-4 thymoma cells. In addition, LLC/IL12 apparently had a much stronger antitumor effect against the established LLC/wt tumor than LLC transduced with B7-1 or GM-CSF cDNA. IL-12 can be considered an efficient candidate molecule for immunogene therapy for lung cancer in this experimental system.
Sumimoto
H
H
Department of Hematology/Oncology, the Institute of Medical Science, the University of Tokyo, Japan.
Tani
K
K
Nakazaki
Y
Y
Tanabe
T
T
Hibino
H
H
Wu
M S
MS
Izawa
K
K
Hamada
H
H
Asano
S
S
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy*; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology; D007121:Immunocompetence; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor